T9CAN Report Summary

This proposal aims to unravel the molecular bases accounting for the anticancer properties of IL-1beta-induced IL-9-producing CD4 T cells (Th9 cells).Th9 cells have been characterized in 2008 as a proinflammatory CD4 T cell subset. While these cells were originally shown to promote inflammation in colitis and asthma, recent work now suggests that these cells also harbor potent anticancer properties. However, the mechanisms leading to the generation of these cells remain incompletely understood. Similarly, the potential contribution of other immune effector cells to the anticancer activity of Th9 cells is elusive. Thus, despite their anticancer properties, the limited knowledge on the ways to control Th9 cell effector functions restricts their putative use for cancer immunotherapy.Our preliminary data indicated that Th9 cells feature superior anticancer properties when induced in the presence of the proinflammatory factor interleukin-1beta (IL-1beta) relatively to Th9 cells obtained in conventional conditions. This striking activity suggested that such Th9 cells play a dominant role in the control of tumor growth. We found that IL-1# does not merely enhance the generation of Th9 cells but selectively induces the expression of the transcription factor IRF1 in developing Th9 cells that dictates their effector functions and anticancer properties.We will have deciphered the molecular series of transcriptional events that ultimately confer anticancer properties to IL-1beta-induced Th9 cells. Specifically, we have identified that the activation of the IL-1R>MyD88>Stat1>Irf1 pathway enhances Th9 cell functions and anticancer activity.Finally, we found that the anticancer efficacy of Th9 cells induced in the presence of IL-1beta depends on IL-21 and on the activation of immune effector NK and CD8 T cells in vivo.These findings provide a mean to modulate the biological activity of Th9 cells to contemplate their use in cancer immunotherapy.